'Bold' Prostate Cancer Trial Enrolls 'Very, Very Quickly' - Medscape

Once the stuff of headlines and clinical buzz, sipuleucel-T (Provenge, Dendreon) has had a steep decline in its profile as a prostate cancer treatment. But the stage is being set for a possible comeback.

To much fanfare in 2010, the drug became the first-ever immunotherapy for metastatic prostate cancer to be approved by the US Food and Drug Administration, albeit in a protracted and controversial process. In the final data set, it improved overall survival by 4 months compared with placebo.

It is an unusual product. Sometimes referred to as a vaccine and usually called by its trade name, Provenge is an autologous active cellular immunotherapy, made individually for each patient.

Clinical uptake of the product was slow, and, after launch, it soon faced stiff competition from other new drugs for advanced disease.

Ten years after approval, the once-hyped therapy is now seldom mentioned, and, according to the company, has only 8% penetration of the metastatic prostate cancer market.

But the manufacturer is planning a hoped-for second act. Now with Chinese ownership, Dendreon is evaluating Provenge, its only product, as a therapy for early prostate cancer among men on active surveillance, a market four times larger than metastatic prostate cancer.

However, a clinical trial exploring this new (and unapproved) use has many questions surrounding it, including its appropriateness for many men.

In the randomized, open-label ProVent trial, American investigators are evaluating whether a 4-6 week treatment with Provenge can reduce disease progression among men on active surveillance compared with surveillance alone over 3 years. The trial is funded by Dendreon.

"This is a bold trial. We're super excited," said principal investigator Neal Shore, MD, Carolina Urologic Research Center in Myrtle Beach, South Carolina.

There's never been a study using an immunotherapeutic in early prostate cancer to slow disease progression, Shore told Medscape Medical News.

"If you can change biologic progression, you can cut down on the number of men who go on to have prostatectomy," he said.

Some men on active surveillance also want to "do something" while being monitored and this represents such a "proactive" therapy, Shore added.

He said that the trial has been very well received by men it is targeting — those with low-risk (Grade Group 1; Gleason score 3+3) and favorable intermediate-risk (Grade Group 2; Gleason score 3+4) prostate cancer.

Enrollment opened in December 2018 and was planned to continue for 1.5 years. But the study reached full accrual of 500-plus patients at 50 sites in less than a year, in October 2019. "It enrolled incredibly fast," Shore said.

"It very, very quickly enrolled," agreed Sam Chang, MD, Vanderbilt University School of Medicine, Nashville, Tennessee, who was approached for comment. That's because it's a low-risk, no-cost, high-benefit (potentially) proposition, he said.

Chang, who is not an investigator in the study, explained that Provenge is "extremely" well tolerated, has a relatively short treatment time, and may prevent some men from having to undergo surgery or radiation. And, importantly, the product — which has a price tag of nearly $100,000 — will be supplied to the trial participants for free. "So why not enroll?" he asked.

But, in the real world, Chang does not see Provenge as a worthwhile gambit for most men on active surveillance.

"You're overtreating the majority of these Gleason score 3+3 patients with [Provenge] — they don't need the medication and do fine without it," he told Medscape Medical News. Also, the risk–benefit equation changes in the real world, when patients have out-of-pocket expenses.

Multiple patient series, including at Johns Hopkins and University of California, San Francisco, have shown that the chance of "significant or problematic" disease progression for Gleason score 3+3 disease is "very low" (10%-15%), with <1% eventually developing metastatic disease, Chang explained.

Furthermore, those men who progress are "just as likely to be cured with surgery if they had been treated prior to progression," he said.

Despite his reservations, Chang does not wholly dismiss the ProVent trial; men with intermediate-risk, Gleason score 3+4 disease are an "intriguing group" for this approach, he said.

Chang asserted that the drug is probably best suited for these intermediate-risk men because they have a higher risk for progression (up to 40%). Preventing that progression would be a "win," because it is associated with worse outcomes (compared with progression with Gleason score 3+3 disease), he said.

Anxiety to Be Recorded

ProVent trial investigator Shore points out that active surveillance is cause for worry for some men.

"Variation in [prostate-specific antigen (PSA)] monitoring and the anxiety of having a 'cancer' diagnosis causes many men to leave surveillance management and undergo interventional treatment," he said in a Dendreon press release last year.

Not everything that prolongs survival has to impact PSA

The ProVent trial will monitor men's anxiety and quality of life throughout the 3-year study period to determine if Provenge, an active treatment for cancer, has any effect on men's psyches and well-being. 

Chang has doubts about Provenge impacting those measures.

He said that a histopathologic endpoint provides a relatively "quick answer" — in 3 years. "But during that time, it may be frustrating for the patient — is this working or not? You don't really know…because it doesn't influence PSA and there are no radiographic changes to be seen," he said.

Shore points out that another treatment approach in advanced prostate cancer — the radiopharmaceutical radium-223 dichloride (Xofigo, Bayer) — does not impact PSA, yet it improves overall survival in men with disease spread to the bones, compared with a placebo.

"Not everything that prolongs survival has to impact PSA," he said.

Shore says that if Provenge can demonstrate a statistically significant difference in grade progression at 3 years compared with standard active surveillance, "that would be an advance that we don't currently have."

Shore is a consultant to multiple genitourinary oncology companies, including Dendreon, and reports research funding from Dendreon and others. Chang reports no relevant financial relationships.

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